Stilbene derivatives for the treatment of CNS and other disorders

ABSTRACT

The present application discloses stilbene derivative compounds and compositions, and methods for treating ocular diseases, neurological disorders and protein aggregation-related disorders in patients using the compounds and compositions as disclosed herein.

TECHNICAL FIELD

Described herein are compounds, compositions and methods for treatmentof ocular diseases, neurological disorders and diseases, and proteinaggregation-related diseases.

BACKGROUND

Presently, there are no known prevention or cure for neurodegenerativediseases or disorders such as Alzheimer's disease (AD), Parkinson'sdisease (PD) and prion diseases (PrDs). It has been demonstrated that anaberrant protein has a propensity to aggregate under certaincircumstances. The present application discloses compounds, compositionsand methods for the treatment of such diseases or disorders.

SUMMARY

Described herein are compounds, compositions and methods for treatmentof ocular diseases, neurological disorders and diseases, and proteinaggregation-related diseases.

Accordingly, described herein is a compound of formula I:

wherein R⁶ is selected from the group consisting of —NR³R⁴, —R³, —OR³and halo; R⁵ is —(CR═CR—)_(n)(CR═CR²—)R¹; n is an integer from 0 to 10,R¹ and R² are independently selected from the group consisting of —H,—CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R, —PO₃HR, and —OPO₃HR,further wherein at least one of R¹ and R² is not —H; each R isindependently selected from —H and C₁₋₆ linear or branched alkyl; and R³and R⁴ are independently selected from the group consisting of H,substituted or unsubstituted linear or branched C₁-C₁₀ alkyl,substituted or unsubstituted phenyl, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted orunsubstituted C₅-C₁₀ cycloalkyl, and substituted or unsubstituted C₅-C₁₀heterocycloalkyl; or R³ and R⁴ attached to their N together form a ringthat is substituted or unsubstituted C₅-C₁₀ heterocycloalkyl, providedthat

-   -   if n=0, and R³ and R⁴ are both: (a) H; (b) substituted or        unsubstituted linear or branched C₁-C₁₀ alkyl; or (c)        substituted or unsubstituted phenyl or C₆-C₁₀ aryl, then R¹ and        R² are not both selected from the group consisting of —H, —CN,        —COOR, and —CONHR.

Also described herein is a pharmaceutical composition comprising atherapeutically effective amount of a compound of formula I as describedabove, and a pharmaceutically acceptable excipient.

Further described herein is a method of treating an ocular disease in apatient in need thereof comprising administering to the patient atherapeutically effective amount of the compound of formula I:

wherein R⁶ is selected from the group consisting of —NR³R⁴, —R³, —OR³and halo; R⁵ is —(CR═CR—)_(n)(CR═CR²—)R¹; n is an integer from 0 to 10,R¹ and R² are independently selected from the group consisting of —H,—CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R, —PO₃HR, and —OPO₃HR,further wherein at least one of R¹ and R² is not —H; each R isindependently selected from —H and C₁₋₆ linear or branched alkyl; and R³and R⁴ are independently selected from the group consisting of H,substituted or unsubstituted linear or branched C₁-C₁₀ alkyl,substituted or unsubstituted phenyl, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted orunsubstituted C₅-C₁₀ cycloalkyl, and substituted or unsubstituted C₅-C₁₀heterocycloalkyl; or R³ and R⁴ attached to their N together form a ringthat is substituted or unsubstituted C₅-C₁₀ heterocycloalkyl, or thecompound

The ocular disease may be selected from the group consisting of maculardegeneration, retinitis pigmentosa, retinopathy, glaucoma and cataracts.

Still further described herein is a method for treating a neurologicaldisorder or disease in a patient in need thereof comprisingadministering to the patient a therapeutically effect amount of thecompound formula I:

wherein R⁶ is selected from the group consisting of —NR³R⁴, —R³, —OR³and halo; R⁵ is —(CR═CR—)_(n)(CR═CR²—)R¹; n is an integer from 0 to 10,R¹ and R² are independently selected from the group consisting of —H,—CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R, —PO₃HR, and —OPO₃HR,further wherein at least one of R¹ and R² is not —H; each R isindependently selected from —H and C₁₋₆ linear or branched alkyl; and R³and R⁴ are independently selected from the group consisting of H,substituted or unsubstituted linear or branched C₁-C₁₀ alkyl,substituted or unsubstituted phenyl, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted orunsubstituted C₅-C₁₀ cycloalkyl, and substituted or unsubstituted C₅-C₁₀heterocycloalkyl; or R³ and R⁴ attached to their N together form a ringthat is substituted or unsubstituted C₅-C₁₀ heterocycloalkyl, or thecompound

The neurological disorder or disease may be a neurodegenerative,neurodevelopmental or neuropsychiatric disorder and further may beselected from the group consisting of Alzheimer's disease (AD),amyotrophic lateral sclerosis (ALS), motor neuron disease, Parkinson'sdisease, Huntington's Disease, prion disease, AIDS or HIV relateddementia, cerebral ischemia, cerebrovascular disease, cerebralhemorrhage, Down syndrome, epilepsy, traumatic brain injury, chronictraumatic encephalopathy, traumatic spinal injury, Friedreich's Ataxia,frontotemporal dementia, hemorrhagic stroke, neurodegeneration withBrain Iron Accumulation, Lewy Body Disease, ischemic stroke, multiplesclerosis, Pick's Disease, progressive supranuclear palsy, seniledementia, mild cognitive impairment, hereditary cerebral hemorrhage,traumatic ischemia attack, lead encephalopathy, subdural hematoma,radiation brain injury, Niemann-Pick Disease and neuronal ceroidlipofuscinoses (NCLs; Batten disease).

Also described herein is a method for inhibiting or reversing proteinaggregation in a patient comprising administering to the patient atherapeutically effective amount of the compound of formula I:

wherein R⁶ is selected from the group consisting of —NR³R⁴, —R³, —OR³and halo; R⁵ is —(CR═CR—)_(n)(CR═CR²—)R¹; n is an integer from 0 to 10,R¹ and R² are independently selected from the group consisting of —H,—CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R, —PO₃HR, and —OPO₃HR,further wherein at least one of R¹ and R² is not —H; each R isindependently selected from —H and C₁₋₆ linear or branched alkyl; and R³and R⁴ are independently selected from the group consisting of H,substituted or unsubstituted linear or branched C₁-C₁₀ alkyl,substituted or unsubstituted phenyl, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted orunsubstituted C₅-C₁₀ cycloalkyl, and substituted or unsubstituted C₅-C₁₀heterocycloalkyl; or R³ and R⁴ attached to their N together form a ringthat is substituted or unsubstituted C₅-C₁₀ heterocycloalkyl, or thecompound

This method is effective to treat a disease selected from the groupconsisting of type 2 diabetes mellitus, Alzheimer's disease (AD),amyotrophic lateral sclerosis (ALS), motor neuron disease, Parkinson'sdisease, Huntington's Disease, Creutzfeldt-Jakob disease and priondisease, or alternatively a disease selected from the group consistingof AA amyloidosis, light chain amyloidosis, familial amyloidpolyneuropathies, AA (Inflammatory) Amyloidosis, amylin relatedamyloidosis, familial visceral amyloidosis, primary cutaneousamyloidosis, cerebral amyloid angiopathy, familial corneal amyloidosisand medullary carcinoma of the thyroid.

DETAILED DESCRIPTION Definitions

Unless specifically noted otherwise herein, the definitions of the termsused are standard definitions used in the art of organic chemistry andpharmaceutical sciences. Exemplary embodiments, aspects and variationsare illustrated in the figures and drawings, and it is intended that theembodiments, aspects and variations, and the figures and drawingsdisclosed herein are to be considered illustrative and not limiting.

While particular embodiments are shown and described herein, it will beobvious to those skilled in the art that such embodiments are providedby way of example only. Numerous variations, changes, and substitutionswill now occur to those skilled in the art. It should be understood thatvarious alternatives to the embodiments described herein may be employedin practicing the methods described herein. It is intended that theappended claims define the scope of the invention and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart. All patents and publications referred to herein are incorporated byreference.

As used in the specification and claims, the singular form “a,” “an,”and “the” include plural references unless the context clearly dictatesotherwise.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

The terms “treatment,” “treating,” “palliating,” and “ameliorating” areused interchangeably herein. These terms refer to an approach forobtaining beneficial or desired results including but not limited totherapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderbeing treated. Also, a therapeutic benefit is achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the patient, notwithstanding that the patient may still beafflicted with the underlying disorder. For prophylactic benefit, thecompositions may be administered to a patient at risk of developing aparticular disease, or to a patient reporting one or more of thephysiological symptoms of a disease, even though a diagnosis of thisdisease may not have been made.

A “therapeutic effect,” as used herein, encompasses a therapeuticbenefit and/or a prophylactic benefit as described above. A prophylacticeffect includes delaying or eliminating the appearance of a disease orcondition, delaying or eliminating the onset of symptoms of a disease orcondition, slowing, halting, or reversing the progression of a diseaseor condition, or any combination thereof.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal so that both agents and/or theirmetabolites are present in the animal at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

A “pharmaceutically acceptable salt” means a salt composition that isgenerally considered to have the desired pharmacological activity, isconsidered to be safe, non-toxic and is acceptable for veterinary andhuman pharmaceutical applications. Pharmaceutically acceptable salts maybe derived from a variety of organic and inorganic counter ions wellknown in the art and include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe molecule contains a basic functionality, salts of organic orinorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. Pharmaceuticallyacceptable acid addition salts can be formed with inorganic acids andorganic acids. Inorganic acids from which salts can be derived include,for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids from which salts canbe derived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like. Organic bases fromwhich salts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, specifically such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. In some embodiments,the pharmaceutically acceptable base addition salt is chosen fromammonium, potassium, sodium, calcium, and magnesium salts.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions describedherein is contemplated. Supplementary active ingredients can also beincorporated into the compositions.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction of a target protein, whether by inhibiting the activity orexpression of the target protein. Accordingly, the terms “antagonist”and “inhibitors” are defined in the context of the biological role ofthe target protein. While preferred antagonists herein specificallyinteract with (e.g. bind to) the target, compounds that inhibit abiological activity of the target protein by interacting with othermembers of the signal transduction pathway of which the target proteinis a member are also specifically included within this definition. Apreferred biological activity inhibited by an antagonist is associatedwith the development, growth, or spread of a tumor, or an undesiredimmune response as manifested in autoimmune disease.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function of a targetprotein, whether by inhibiting the activity or expression of the targetprotein. Accordingly, the term “agonist” is defined in the context ofthe biological role of the target polypeptide. While preferred agonistsherein specifically interact with (e.g. bind to) the target, compoundsthat initiate or enhance a biological activity of the target polypeptideby interacting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

As used herein, “agent” or “biologically active agent” refers to abiological, pharmaceutical, or chemical compound or other moiety.Non-limiting examples include simple or complex organic or inorganicmolecule, a peptide, a protein, an oligonucleotide, an antibody, anantibody derivative, antibody fragment, a vitamin derivative, acarbohydrate, a toxin, or a chemotherapeutic compound. Various compoundscan be synthesized, for example, small molecules and oligomers (e.g.,oligopeptides and oligonucleotides), and synthetic organic compoundsbased on various core structures. In addition, various natural sourcescan provide compounds for screening, such as plant or animal extracts,and the like. A skilled artisan can readily recognize the limits to thestructural nature of the agents described herein.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “selective inhibition” or “selectively inhibit” as applied to abiologically active agent refers to the agent's ability to selectivelyreduce the target signaling activity as compared to off-target signalingactivity, via direct or interact interaction with the target.

“Subject” refers to an animal, such as a mammal, for example a human.The methods described herein can be useful in both human therapeuticsand veterinary applications. In some embodiments, the patient is amammal, and in some embodiments, the patient is human.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14,and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press, 1987, both ofwhich are incorporated in full by reference herein. The term “prodrug”is also meant to include any covalently bonded carriers, which releasethe active compound in vivo when such prodrug is administered to amammalian subject. Prodrugs of an active compound, as described herein,may be prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of an alcohol or acetamide, formamide and benzamidederivatives of an amine functional group in the active compound and thelike.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assay runoutside of a subject assay. In vitro assays encompass cell-based assaysin which cells alive or dead are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds as described hereinwherein one or more hydrogens are replaced by deuterium or tritium, orthe replacement of one or more carbon atoms by the ¹³C- or ¹⁴C-enrichedcarbon isotope. Further, substitution with heavier isotopes,particularly deuterium (²H or D) may afford certain therapeuticadvantages resulting from greater metabolic stability, increased in vivohalf-life, reduced dosage requirements or an improvement in therapeuticindex. It is understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I).

The compounds described herein may also contain unnatural proportions ofatomic isotopes at one or more of atoms that constitute such compounds.For example, the compounds may be radiolabeled with radioactiveisotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C). All isotopic variations of the compounds describedherein, whether radioactive or not, are encompassed.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are a pair of stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term “(..+−..)” is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon can bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers and can thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat can be defined, in terms of absolute stereochemistry, as (R)- or(S)-. The present chemical entities, pharmaceutical compositions andmethods are meant to include all such possible isomers, includingracemic mixtures, optically pure forms and intermediate mixtures.Optically active (R)- and (S)-isomers can be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.The optical activity of a compound can be analyzed via any suitablemethod, including but not limited to chiral chromatography andpolarimetry, and the degree of predominance of one stereoisomer over theother isomer can be determined.

When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.

A “substituted” or “optionally substituted” group, means that a group(such as alkyl, aryl, heterocyclyl, cycloalkyl, hetrocyclylalkyl,arylalkyl, heteroaryl, or heteroarylalkyl) unless specifically notedotherwise, may have 1, 2 or 3 —H groups substituted by 1, 2 or 3substituents selected from halo, trifluoromethyl, trifluoromethoxy,methoxy, —COOH, —CHO, —NH₂, —NO₂, —OH, —SH, —SMe, —NHCH₃, —N(CH₃)₂, —CNand the like.

“Tautomers” are structurally distinct isomers that interconvert bytautomerization. “Tautomerization” is a form of isomerization andincludes prototropic or proton-shift tautomerization, which isconsidered a subset of acid-base chemistry. “Prototropictautomerization” or “proton-shift tautomerization” involves themigration of a proton accompanied by changes in bond order, often theinterchange of a single bond with an adjacent double bond. Wheretautomerization is possible (e.g. in solution), a chemical equilibriumof tautomers can be reached. An example of tautomerization is keto-enoltautomerization. A specific example of keto-enol tautomerization is theinterconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-onetautomers. Another example of tautomerization is phenol-ketotautomerization. A specific example of phenol-keto tautomerization isthe interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

Compounds described herein also include crystalline and amorphous formsof those compounds, including, for example, polymorphs,pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms of thecompounds, as well as mixtures thereof. “Crystalline form,” “polymorph,”and “novel form” may be used interchangeably herein, and are meant toinclude all crystalline and amorphous forms of the compound listedabove, as well as mixtures thereof, unless a particular crystalline oramorphous form is referred to.

“Solvent,” “organic solvent,” and “inert solvent” each means a solventinert under the conditions of the reaction being described inconjunction therewith including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, N-methylpyrrolidone (“NMP”), pyridine and the like. Unlessspecified to the contrary, the solvents used in the reactions describedherein are inert organic solvents. Unless specified to the contrary, foreach gram of the limiting reagent, one cc (or mL) of solvent constitutesa volume equivalent.

Compositions

Described herein are compounds of formula I:

wherein R⁶ is selected from the group consisting of —NR³R⁴, —R³, —OR³and halo; R⁵ is —(CR═CR—)_(n)(CR═CR²—)R¹;n is an integer from 0 to 10;R¹ and R² are independently selected from the group consisting of —H,—CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R, —PO₃HR, and —OPO₃HR,further wherein at least one of R¹ and R² is not —H;each R is independently selected from —H and C₁₋₆ linear or branchedalkyl; andR³ and R⁴ are independently selected from the group consisting of H,substituted or unsubstituted linear or branched C₁-C₁₀ alkyl,substituted or unsubstituted phenyl, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted C₅-C₁ heteroaryl, substituted orunsubstituted C₅-C₁₀ cycloalkyl, and substituted or unsubstituted C₅-C₁₀heterocycloalkyl; or N, R³ and R⁴ together form a ring that issubstituted or unsubstituted C₅-C₁₀ heterocycloalkyl, provided that

-   -   if n=0, and R³ and R⁴ are both: (a) H; (b) substituted or        unsubstituted linear or branched C₁-C₁₀ alkyl; or (c)        substituted or unsubstituted phenyl or C₆-C₁₀ aryl, then R¹ and        R² are not both selected from the group consisting of —H, —CN,        —COOR, and —CONHR.

In preferred embodiments, the compound may be of formula II, III or IV:

where R⁵ and R⁶ are as described in the preceding paragraph.

The structures of the compounds described herein, as shown in formulaeI-IV, have a central stilbene structure with two substituent moieties,R⁵ and R⁶, attached thereto. One substituent moiety is attached to anyposition on each of the phenyl moieties, as shown in formula I. Inpreferred embodiments, the substituent moieties are attached topreferred positions on the phenyl moieties as shown in formulae II-IV.

In general, the substituent moiety R⁶ will be a pi electron-donatingmoiety, and the other substituent moiety R⁵ will be a pielectron-withdrawing moiety. The pi electron-donating moiety ispreferably an amino, alkyl or alkoxy moiety represented herein by—NR³R⁴, —R³, or —OR³. A particularly preferred pi electron-donatingmoiety is the amino moiety —NR³R⁴, and in an even more preferredembodiment is selected from the group consisting of diethylamino,diphenylamino, methyl(phenyl)amino, cyclohexyl(methyl)amino,bis(4-methoxyphenyl)amino, bis(4-(tert-butyl)phenyl)amino,di(pyridin-2-yl)amino, di(pyridin-3-yl)amino, di(pyridin-4-yl)amino,piperidin-1-yl, 4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl,pyrrolidin-1-yl, and morpholino. In other preferred embodiments, the pielectron-donating moiety is —R³, or —OR³, and preferably selected fromthe group consisting of 3′,4′-dimethoxyphenyl, tert-butyl, phenyoxy, andmethoxy. In still another preferred embodiment, the pi electron-donatingmoiety is halo selected from fluoro, bromo, chloro, and iodo, mostpreferably bromo.

The pi electron-withdrawing moiety R⁵ may be —H, —CN, —COOR, CONHR,CON(H)OR, —SO₃R, —SO₂R—OSO₃R, —PO₃HR, or —OPO₃HR, and maybe directlyattached to the central structure, or linked via from one to about tenconjugated carbon-carbon double bonds. This moiety is represented hereinby the structure —(CR═CR—)_(n)(CR═CR²—)R¹, wherein n is an integer from0 to 10; and R¹ and R² are independently selected from the groupconsisting of —H, —CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R,—PO₃HR, or —OPO₃HR, further wherein at least one of R¹ and R² is not —H.As used herein, each R is independently selected from —H and C₁₋₆ linearor branched alkyl. In a particular preferred embodiment, R¹ and R²together are —CN and —COOH, n=0 and m=1.

In the compounds described herein, R³ and R⁴ are independently selectedfrom the group consisting of H, substituted or unsubstituted linear orbranched C₁-C₁₀ alkyl, substituted or unsubstituted phenyl, substitutedor unsubstituted C₆-C₁₀ aryl, substituted or unsubstituted C₅-C₁₀heteroaryl, substituted or unsubstituted C₅-C₁₀ cycloalkyl, andsubstituted or unsubstituted C₅-C₁₀ heterocycloalkyl; or N, R³ and R⁴together form a ring that is substituted or unsubstituted C₅-C₁₀heterocycloalkyl. In particularly preferred embodiments, R³ and R⁴ aremethyl, ethyl, cyclohexyl, phenyl, 4-methoxyphenyl,4-(tert-butyl)phenyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, or N,R³ and R⁴ together are piperidin-1-yl, 4-methylpiperazin-1-yl,4-phenylpiperazin-1-yl, pyrrolidin-1-yl, or morpholino.

The following preferred compounds of the invention have beensynthesized:

Entry Structure Compound # 1

WBI-PC-63 2

WBI-PC-64 3

WBI-PC-66 4

WBI-PC-81 5

WBI-PC-174 6

WBI-PC-78 7

WBI-PC-190 8

WBI-PC-191 9

WBI-PC-192

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation procedurescan be had by reference to the examples herein. However, otherequivalent separation or isolation procedures can also be used.

When desired, the (R)- and (S)-isomers of the compounds describedherein, if present, may be resolved by methods known to those skilled inthe art, for example by formation of diastereomeric salts or complexeswhich may be separated, for example, by crystallization; via formationof diastereomeric derivatives which may be separated, for example, bycrystallization, gas-liquid or liquid chromatography; selective reactionof one enantiomer with an enantiomer-specific reagent, for exampleenzymatic oxidation or reduction, followed by separation of the modifiedand unmodified enantiomers; or gas-liquid or liquid chromatography in achiral environment, for example on a chiral support, such as silica witha bound chiral ligand or in the presence of a chiral solvent.Alternatively, a specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer to the other by asymmetrictransformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Pharmaceutically acceptable forms of the compounds recited hereininclude pharmaceutically acceptable salts, chelates, non-covalentcomplexes or derivatives, prodrugs, and mixtures thereof. In certainembodiments, the compounds described herein are in the form ofpharmaceutically acceptable salts. In addition, if the compounddescribed herein is obtained as an acid addition salt, the free base canbe obtained by basifying a solution of the acid salt. Conversely, if theproduct is a free base, an addition salt, particularly apharmaceutically acceptable addition salt, may be produced by dissolvingthe free base in a suitable organic solvent and treating the solutionwith an acid, in accordance with conventional procedures for preparingacid addition salts from base compounds. Those skilled in the art willrecognize various synthetic methodologies that may be used to preparenon-toxic pharmaceutically acceptable addition salts.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary from, for example, between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) include thoseembodiments, for example, an embodiment of any composition of matter,composition, method, or process, or the like, that “consist of” or“consist essentially of” the described features.

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of Formula I asthe active ingredient, or a pharmaceutically acceptable salt, ester,prodrug, solvate, hydrate or derivative thereof. Where desired, thepharmaceutical compositions contain pharmaceutically acceptable saltand/or coordination complex thereof, and one or more pharmaceuticallyacceptable excipients, carriers, including inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desired,a compound of Formula I and other agent(s) may be mixed into apreparation or both components may be formulated into separatepreparations to use them in combination separately or at the same time.A compound as described herein may also be used in combination withother agents, e.g., an additional disaggregating agent that is or is notof Formula I, for treatment of a the diseases listed herein in asubject. Suitable agents for use in combination with the compoundsdescribed herein, including compounds of Formula (I) and subgenerathereof, include compounds of the formula:

wherein: X¹ is —OR¹ or —NR¹R²; X² is selected from the group consistingof —NR³—, —O— and —S(O)₁₋₂—; A¹ is selected from the group consisting of—C(R⁴R⁵)—, —C(O)—, —C(S)— and —C(NR⁶)—; A² is selected from the groupconsisting of —C(R⁷R⁸)—, —C(O)—, —C(S)— and —C(NR⁹)—; R¹ and R² are eachindependently H, substituted or unsubstituted C₁₋₆ alkyl, X—C₁₋₆ alkyl,substituted or unsubstituted C₅₋₁₀ aryl, substituted or unsubstituted—C₁₋₆ alkyl-C₆₋₁₀ aryl, substituted or unsubstituted C₁₋₆ alkyC(O)—,X—C₁₋₆ alkyC(O)—, substituted or unsubstituted C₁₋₆ alkylS(O)₁₋₂—,substituted or unsubstituted C₁₋₆ alkylNR′C(O)—, X—C₁₋₆ alkylNR′C(O)—,X—C₁₋₆ alkoxyC(NR″)— and substituted or unsubstituted C₁₋₆alkoxyC(NR″)—; R′ and R″ are each independently selected from the groupconsisting of H, substituted or unsubstituted C₁₋₆ alkyl and substitutedand unsubstituted —C₁₋₆ alkyl-C₆₋₁₀ aryl; R³ is H or selected from thegroup consisting of substituted or unsubstituted C₁₋₆ alkyl, substitutedor unsubstituted C₅₋₁₀ aryl, substituted or unsubstituted —C₁₋₆alkyl-C₆₋₁₀ aryl, substituted or unsubstituted —C₁₋₆ alkyl-C₅₋₁₀heteroaryl, substituted or unsubstituted C₁₋₆ alkylC(O)—, substituted orunsubstituted C₁₋₆ alkyl-S(O)₁₋₂—, substituted or unsubstituted C₁₋₆alkylNHC(O)— and substituted or unsubstituted C₁₋₆ alkoxyC(NR′)—; R⁴, R,R⁶, R⁷, R⁸ and R⁹ are each independently H or selected from the groupconsisting of substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₁₋₆ alkylC(O)—, substituted or unsubstituted C₁₋₆alkoxyC(O)—, substituted or unsubstituted —C₁₋₆ alkyl-C₆₋₁₀ aryl andsubstituted or unsubstituted C₅₋₁₀ aryl; R¹⁰, R¹¹ and R¹² are eachindependently H or selected from the group consisting of substituted orunsubstituted C₁₋₆ alkyl, X—C₁₋₆alkyl, X—C₁₋₆ alkylC(O)— and substitutedor unsubstituted C₁₋₆ alkylC(O)—; R¹³ is H or is selected from the groupconsisting of X, halo, —OR′, —CN, —SR′, —NR′R″, —NO₂, —CO₂R′, —SO₃R′,substituted or unsubstituted C₁₋₆ alkyl, C₁₋₆ alkyl-X, —C₁₋₆ alkyl-SH,substituted or unsubstituted C₁₋₆ alkoxy-, substituted or unsubstitutedC₁₋₆ alkylC(O)—, X—C₁₋₆ alkylC(O)—, substituted or unsubstituted C₁₋₆alkylC(S)—, X—C₁₋₆ alkylC(S)—, —(CH₂)_(n)—NH—(CH₂)_(m)—NR′R″, C₁₋₆alkylC(NR′)—, X—C₁₋₆ alkylC(NR′)—, X—C₁₋₆ alkylC(NOH)—, C₁₋₆alkylC(NOH)—, —(CH₂)_(n)—C(NOH)—C₁₋₆ alkyl, C₅₋₁₀ aryl, —C₁₋₆alkyl-C₆₋₁₀ aryl, —C₁₋₆ alkyl-C₃₋₁₀ heteroaryl, and —C₃₋₁₀ heteroaryl;each X is independently selected from the group consisting of ¹³¹I,¹²⁴I, ¹²⁵I, ³H, ¹²³I, ¹⁸F, ¹⁹F, ¹¹C, ⁷⁵Br, ¹³C, ¹³N, ¹⁵O and ⁷⁶Br; and mand n are each independently 1, 2 or 3. Suitable compounds of thisformula are described in WO2014/052906.

In some embodiments, the concentration of one or more of the compoundsof Formula I in the pharmaceutical compositions described herein is lessthan 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%,15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%,0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%,0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%,0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsof Formula I is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more of the compoundsof Formula I is in the range from approximately 0.0001% to approximately50%, approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 28%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%,approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24%, approximately 0.08% to approximately 23%,approximately 0.09% to approximately 22%, approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 14%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsof Formula I is in the range from approximately 0.001% to approximately10%, approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more of the compounds ofFormula I is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g,2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g,0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g,0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of one or more of the compounds ofFormula I is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g,0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g,7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

In some embodiments, the amount of one or more of the compounds ofFormula I is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

The compounds of Formula I described herein are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, andfrom 5 to 40 mg per day are examples of dosages that may be used. Anexemplary dosage is 10 to 30 mg per day. The exact dosage will dependupon the route of administration, the form in which the compound ofFormula I is administered, the subject to be treated, the body weight ofthe subject to be treated, and the preference and experience of theattending physician.

A pharmaceutical composition described herein typically contains anactive ingredient (e.g., a compound of Formula I or a pharmaceuticallyacceptable salt and/or coordination complex thereof), and one or morepharmaceutically acceptable excipients, carriers, including but notlimited to inert solid diluents and fillers, diluents, sterile aqueoussolution and various organic solvents, permeation enhancers,solubilizers and adjuvants.

Described below are non-limiting exemplary pharmaceutical compositionsand methods for preparing the same.

Pharmaceutical Compositions for Oral Administration

Described herein is a pharmaceutical composition for oral administrationcontaining a compound of Formula I:

wherein R⁶ is selected from the group consisting of —NR³R⁴, —R³, —OR³and halo; R⁵ is —(CR═CR—)_(n)(CR═CR²—)R¹; n is an integer from 0 to 10,R¹ and R² are independently selected from the group consisting of —H,—CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R, —PO₃HR, and —OPO₃HR,further wherein at least one of R¹ and R² is not —H; each R isindependently selected from —H and C₁₋₆ linear or branched alkyl; and R³and R⁴ are independently selected from the group consisting of H,substituted or unsubstituted linear or branched C₁-C₁₀ alkyl,substituted or unsubstituted phenyl, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted C₅-C₁ heteroaryl, substituted orunsubstituted C₅-C₁₀ cycloalkyl, and substituted or unsubstituted C₅-C₁₀heterocycloalkyl; or R³ and R⁴ attached to their N together form a ringthat is substituted or unsubstituted C₅-C₁₀ heterocycloalkyl, providedthat

-   -   if n=0, and R³ and R⁴ are both: (a) H; (b) substituted or        unsubstituted linear or branched C₁-C₁₀ alkyl; or (c)        substituted or unsubstituted phenyl or C₆-C₁₀ aryl, then R¹ and        R² are not both selected from the group consisting of —H, —CN,        —COOR, and —CONHR,        and a pharmaceutical excipient suitable for oral administration.

Also described herein is a solid pharmaceutical composition for oraladministration containing: (i) an effective amount of a compound ofFormula I; optionally (ii) an effective amount of a second agent; and(iii) a pharmaceutical excipient suitable for oral administration. Insome embodiments, the composition further contains: (iv) an effectiveamount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions suitable for oral administration can be presented asdiscrete dosage forms, such as capsules, cachets, or tablets, or liquidsor aerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion. Such dosage forms can be prepared by anyof the methods of pharmacy, but all methods include the step of bringingthe active ingredient into association with the carrier, whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

Also described herein are anhydrous pharmaceutical compositions anddosage forms comprising an active ingredient, since water can facilitatethe degradation of some compounds. For example, water may be added(e.g., 5%) in the pharmaceutical arts as a means of simulating long-termstorage in order to determine characteristics such as shelf-life or thestability of formulations over time. Anhydrous pharmaceuticalcompositions and dosage forms can be prepared using anhydrous or lowmoisture containing ingredients and low moisture or low humidityconditions. Pharmaceutical compositions and dosage forms which containlactose can be made anhydrous if substantial contact with moistureand/or humidity during manufacturing, packaging, and/or storage isexpected. An anhydrous pharmaceutical composition may be prepared andstored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions may be packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the compositions for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols; or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions described herein toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) maybe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used may vary based upon the type of formulationand mode of administration, and may be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, maybe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms include, butare not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, calcium stearate,magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, stearic acid, sodiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the essential active ingredient therein may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if so desired, emulsifying and/or suspending agents, together withsuch diluents as water, ethanol, propylene glycol, glycerin, and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin, or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, hydrophilic surfactants,lipophilic surfactants, and mixtures thereof. That is, a mixture ofhydrophilic surfactants may be employed, a mixture of lipophilicsurfactants may be employed, or a mixture of at least one hydrophilicsurfactant and at least one lipophilic surfactant may be employed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate,sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octylphenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound described hereinand to minimize precipitation of the compound described herein. This canbe especially important for compositions for non-oral use, e.g.,compositions for injection. A solubilizer may also be added to increasethe solubility of the hydrophilic drug and/or other components, such assurfactants, or to maintain the composition as a stable or homogeneoussolution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, 8-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a patientusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%,50%, 100%, or up to about 200% by weight, based on the combined weightof the drug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%, 2%, 1% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals, alkaline earth metals, and the like. Example may include,but not limited to, sodium, potassium, lithium, magnesium, calcium andammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical Compositions for Injection.

Described herein are pharmaceutical compositions for injectioncontaining a compound of Formula I:

wherein R⁶ is selected from the group consisting of —NR³R⁴, —R³, —OR³and halo; R⁵ is —(CR═CR—)_(n)(CR═CR²—)R¹; n is an integer from 0 to 10,R¹ and R² are independently selected from the group consisting of —H,—CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R, —PO₃HR, and —OPO₃HR,further wherein at least one of R¹ and R² is not —H; each R isindependently selected from —H and C₁₋₆ linear or branched alkyl; and R³and R⁴ are independently selected from the group consisting of H,substituted or unsubstituted linear or branched C₁-C₁₀ alkyl,substituted or unsubstituted phenyl, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted orunsubstituted C₅-C₁₀ cycloalkyl, and substituted or unsubstituted C₅-C₁₀heterocycloalkyl; or R³ and R⁴ attached to their N together form a ringthat is substituted or unsubstituted C₅-C₁₀ heterocycloalkyl, providedthat

-   -   if n=0, and R³ and R⁴ are both: (a) H; (b) substituted or        unsubstituted linear or branched C₁-C₁₀ alkyl; or (c)        substituted or unsubstituted phenyl or C₆-C₁₀ aryl, then R¹ and        R² are not both selected from the group consisting of —H, —CN,        —COOR, and —CONHR,        and a pharmaceutical excipient suitable for injection.        Components and amounts of agents in the compositions are as        described herein.

The forms in which the novel compositions described herein may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compound ofFormula I in the required amount in the appropriate solvent with variousother ingredients as enumerated above, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thevarious sterilized active ingredients into a sterile vehicle whichcontains the basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, certain desirable methodsof preparation are vacuum-drying and freeze-drying techniques whichyield a powder of the active ingredient plus any additional desiredingredient from a previously sterile-filtered solution thereof.

Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery.

Also described herein is a pharmaceutical composition for transdermaldelivery containing a compound of Formula I:

wherein R⁶ is selected from the group consisting of —NR³R⁴, —R³, —OR³and halo; R⁵ is —(CR═CR—)_(n)(CR═CR²—)R¹; n is an integer from 0 to 10,R¹ and R² are independently selected from the group consisting of —H,—CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R, —PO₃HR, and —OPO₃HR,further wherein at least one of R¹ and R² is not —H; each R isindependently selected from —H and C₁₋₆ linear or branched alkyl; and R³and R⁴ are independently selected from the group consisting of H,substituted or unsubstituted linear or branched C₁-C₁₀ alkyl,substituted or unsubstituted phenyl, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted orunsubstituted C₅-C₁₀ cycloalkyl, and substituted or unsubstituted C₅-C₁₀heterocycloalkyl; or R³ and R⁴ attached to their N together form a ringthat is substituted or unsubstituted C₅-C₁₀ heterocycloalkyl, providedthat

-   -   if n=0, and R³ and R⁴ are both: (a) H; (b) substituted or        unsubstituted linear or branched C₁-C₁₀ alkyl; or (c)        substituted or unsubstituted phenyl or C₆-C₁₀ aryl, then R¹ and        R² are not both selected from the group consisting of —H, —CN,        —COOR, and —CONHR,        and a pharmaceutical excipient suitable for transdermal        delivery.

Compositions described herein can be formulated into preparations insolid, semi-solid, or liquid forms suitable for local or topicaladministration, such as gels, water soluble jellies, creams, lotions,suspensions, foams, powders, slurries, ointments, solutions, oils,pastes, suppositories, sprays, emulsions, saline solutions, ordimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods described hereinemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion of acompound of Formula I in controlled amounts, either with or withoutanother agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on-demand delivery of pharmaceuticalagents.

Pharmaceutical Compositions for Inhalation.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

Other Pharmaceutical Compositions.

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical compositions are well-known in the art. See, e.g.,Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology,Ninth Edition, McGraw Hill, 2004; Goodman and Gilman, eds., ThePharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams &Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-SecondEdition (The Pharmaceutical Press, London, 1999); all of which areincorporated by reference herein in their entirety.

Administration of the compounds of Formula I or pharmaceuticalcompositions described herein can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion), topical (e.g. transdermal application),rectal administration, via local delivery by catheter or stent orthrough inhalation. Compounds can also be administered intraadiposallyor intrathecally.

The amount of a compound of Formula I administered will be dependent onthe mammal being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to 7 g/day,preferably about 0.05 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, e.g. by dividing such largerdoses into several small doses for administration throughout the day.

In some embodiments, a compound of Formula I is administered in a singledose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes may be used as appropriate.

In some embodiments, a compound of Formula I is administered in multipledoses. Dosing may be about once, twice, three times, four times, fivetimes, six times, or more than six times per day. Dosing may be aboutonce a month, once every two weeks, once a week, or once every otherday. In another embodiment a compound and another agent are administeredtogether about once per day to about 6 times per day. In anotherembodiment the administration of a compound of Formula I and an agentcontinues for less than about 7 days. In yet another embodiment theadministration continues for more than about 6, 10, 14, 28 days, twomonths, six months, or one year. In some cases, continuous dosing isachieved and maintained as long as necessary.

Administration of the compound(s) of Formula I may continue as long asnecessary. In some embodiments, a compound of Formula I is administeredfor more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments,a compound of Formula I is administered for less than 28, 14, 7, 6, 5,4, 3, 2, or 1 day. In some embodiments, a compound of Formula I isadministered chronically on an ongoing basis, e.g., for the treatment ofchronic effects.

An effective amount of a compound of Formula I may be administered ineither single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compositions described herein may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. A compound of Formula I may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of Formula I is admixed with a matrix.Such a matrix may be a polymeric matrix, and may serve to bond thecompound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester)copolymers (e.g. PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be non-degrading or may degrade with time,releasing the compound or compounds. A compound of Formula I may beapplied to the surface of the stent by various methods such as dip/spincoating, spray coating, dip-coating, and/or brush-coating. The compoundsmay be applied in a solvent and the solvent may be allowed to evaporate,thus forming a layer of compound onto the stent. Alternatively, acompound of Formula I may be located in the body of the stent or graft,for example in microchannels or micropores. When implanted, the compounddiffuses out of the body of the stent to contact the arterial wall. Suchstents may be prepared by dipping a stent manufactured to contain suchmicropores or microchannels into a solution of a compound of Formula Iin a suitable solvent, followed by evaporation of the solvent. Excessdrug on the surface of the stent may be removed via an additional briefsolvent wash. In yet other embodiments, a compound of Formula I may becovalently linked to a stent or graft. A covalent linker may be usedwhich degrades in vivo, leading to the release of a compound of FormulaI. Any bio-labile linkage may be used for such a purpose, such as ester,amide or anhydride linkages. A compound of Formula I may additionally beadministered intravascularly from a balloon used during angioplasty.Extravascular administration of a compound of Formula I via the pericardor via adventitial application of formulations described herein may alsobe performed to decrease restenosis.

A variety of stent devices which may be used as described are disclosed,for example, in the following references, all of which are herebyincorporated by reference: U.S. Pat. Nos. 5,451,233; 5,040,548;5,061,273; 5,496,346; 5,292,331; 5,674,278; 3,657,744; 4,739,762;5,195,984; 5,292,331; 5,674,278; 5,879,382; 6,344,053.

The compounds of Formula I may be administered in dosages. It is knownin the art that due to inter-subject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy. Dosing for a compound of Formula I may be found byroutine experimentation in light of the instant disclosure.

When a compound of Formula I, is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of Formula I unit dose forms of the agent and the compoundof Formula I may be adjusted accordingly.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, or suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound of Formula I as an activeingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Kits are also described herein. The kits include one or more compoundsof Formula I as described herein, in suitable packaging, and writtenmaterial that can include instructions for use, discussion of clinicalstudies, listing of side effects, and the like. Such kits may alsoinclude information, such as scientific literature references, packageinsert materials, clinical trial results, and/or summaries of these andthe like, which indicate or establish the activities and/or advantagesof the composition, and/or which describe dosing, administration, sideeffects, drug interactions, or other information useful to the healthcare provider. Such information may be based on the results of variousstudies, for example, studies using experimental animals involving invivo models and studies based on human clinical trials. The kit mayfurther contain another agent. In some embodiments, a compound ofFormula I and the agent are provided as separate compositions inseparate containers within the kit. In some embodiments, the compounddescribed herein and the agent are provided as a single compositionwithin a container in the kit. Suitable packaging and additionalarticles for use (e.g., measuring cup for liquid preparations, foilwrapping to minimize exposure to air, and the like) are known in the artand may be included in the kit. Kits described herein can be provided,marketed and/or promoted to health providers, including physicians,nurses, pharmacists, formulary officials, and the like. Kits may also,in some embodiments, be marketed directly to the consumer.

Therapeutic Methods

The compounds and pharmaceutical compositions described herein, intherapeutically effective amounts and as described above, are useful inmethods to treat ocular diseases, neurological diseases, and proteinaggregation-related diseases.

The therapeutic methods described herein comprise the step ofadministering a therapeutically effective amount of the compound

or a compound of formula I:

wherein R⁶ is selected from the group consisting of —NR³R⁴, —R³, —OR³and halo;R⁵ is —(CR═CR—)_(n)(CR═CR²—)R¹;n is an integer from 0 to 10;R¹ and R² are independently selected from the group consisting of —H,—CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R, —PO₃HR, and —OPO₃HR,further wherein at least one of R¹ and R² is not —H;each R is independently selected from —H and C₁₋₆ linear or branchedalkyl; andR³ and R⁴ are independently selected from the group consisting of H,substituted or unsubstituted linear or branched C₁-C₁₀ alkyl,substituted or unsubstituted phenyl, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substituted orunsubstituted C₅-C₁₀ cycloalkyl, and substituted or unsubstituted C₅-C₁₀heterocycloalkyl; or N, R³ and R⁴ together form a ring that issubstituted or unsubstituted C₅-C₁₀ heterocycloalkyl.

In preferred embodiments, the compound may be of formula II, III or IV:

where R⁵ and R⁶ are as described in the preceding paragraph.

In one embodiment, the therapeutically effective amount of a compounddescribed above is used in methods to treat an ocular disease selectedfrom the group consisting of macular degeneration, retinitis pigmentosa,retinopathy, glaucoma and cataracts.

In another embodiment, the therapeutically effective amount of acompound described above is used in methods to treat a neurologicaldisorder or disease or a neurodegenerative disease.

In one aspect of the above, the neurological disorder or disease is aneurodegenerative, neurodevelopmental or neuropsychiatric disorder. Inanother aspect of the above method, the neurodegenerative disorder ordisease is selected from the group consisting of Alzheimer's disease(AD), amyotrophic lateral sclerosis (ALS), motor neuron disease,Parkinson's disease, Huntington's Disease, prion disease, AIDS or HIVrelated dementia, cerebral ischemia, cerebrovascular disease, cerebralhemorrhage, Down Syndrome, epilepsy, traumatic brain injury, chronictraumatic encephalopathy, traumatic spinal injury, Friedreich's Ataxia,frontotemporal dementia, hemorrhagic stroke, Neurodegeneration withBrain Iron Accumulation, Lewy Body Disease, ischemic stroke, multiplesclerosis, Pick's Disease, progressive supranuclear palsy, seniledementia, mild cognitive impairment, hereditary cerebral hemorrhage,traumatic ischemia attack, lead encephalopathy, subdural hematoma,radiation brain injury, Niemann-Pick Disease and neuronal ceroidlipofuscinoses (NCLs; Batten disease).

In another embodiment, the therapeutically effective amount of acompound described above is used in methods to inhibit proteinaggregation in a patient with a protein aggregation-related disease. Inone aspect of the above method, the disease is selected from the groupconsisting of type 2 diabetes mellitus, Alzheimer's disease (AD),amyotrophic lateral sclerosis (ALS), motor neuron disease, Parkinson'sdisease, Huntington's Disease, Creutzfeldt-Jacob disease and priondisease. In another aspect, the therapeutically effective amount iseffective to treat a disease selected from the group consisting of AAamyloidosis, light chain amyloidosis, familial amyloid polyneuropathies,AA (Inflammatory) Amyloidosis, amylin related amyloidosis, familialvisceral amyloidosis, primary cutaneous amyloidosis, cerebral amyloidangiopathy, familial corneal amyloidosis and medullary carcinoma of thethyroid.

EXPERIMENTAL

All reagents were purchased from commercial suppliers and used assupplied unless stated otherwise. Reactions were carried out in airunless stated otherwise. 400 MHz ¹H NMR spectra were obtained on a JEOLAS 400 spectrometer. Low-resolution mass spectra (LRMS) were obtained ona JEOL JMS-T100LC DART/AccuTOF mass spectrometer. Measurement ofreversal of protein aggregation may be carried out using such assays asBis-ANS Fluorescence as described in, for example, W. T. Chen et al., J.Biol. Chem, 2011, 286 (11), 9646.

General synthetic scheme for making the compounds herein:

Example 1 Synthesis of(Z)-3-[4-[(E)-2-[4-(4-tert-butyl-N-(4-tert-butylphenyl)anilino)phenyl]vinyl]-2,5-dimethoxy-phenyl]-2-cyano-prop-2-enoicAcid (WBI-PC-63)

This is the synthetic scheme for Example 1.

Synthesis of Olefin Intermediate A

To a mixture of Bis((4-t-butyl)phenyl)amine (15.0 g, 0.053 mol) and4-bromostyrene (˜7 mL, 0.053 mol, 1 equiv.) in an oven dried 500 mLSchlenck flask was added Pd₂(dba)₃ (488 mg, 0.533 mmol), phosphine (360mg, 1.06 mmol) and NaOtBu (5.63 g, 0.059 mol). The flask was flushedwith N₂ for 10 min, treated with degassed 1,4-dioxane (50 mL) and themixture was heated to 80° C. for 1.5 hours under N₂. The reaction wasmonitored by TLC for completion before cooling to room temperature. Theorganic layer was washed with DI water (2×100 mL) and then saturatedbrine solution (100 mL). The combined organic layer was then dried withanhydrous Na₂SO₄ and concentrated. The resulting crude olefin was useddirectly in the following step without further purification.

Synthesis of Aldehyde Intermediate B

To the dark brown olefin (olefin intermediate A) in the Schlenck flaskunder N₂ was added 4-bromo-2,5-dimethoxy benzaldehyde (13.0 g, 0.053mol), N-methyl-dicylohexyl amine (23 mL, 0.112 mol), Pd₂(dba)₃ (488 mg,0.533 mmol), and the phosphine salt (307 mg, 1.06 mmol) under N₂. Dryand degassed 1,4-dioxane (25 mL) was then added to the flask and themixture was stirred at 60° C. under N₂ for 2.5 hours. The mixture turnedfrom purple to yellow green during the course of the reaction. CrudeLCMS showed the reaction was complete, and the mixture was filtered andthe collected solid washed with copious amounts of CH₂Cl₂ to separatethe product from the inorganic materials. The combined CH₂Cl₂/dioxanelayer was concentrated under reduced pressure. The resulting orange-redresidue was dissolved in CH₂Cl₂ (60 mL) and washed with 1N HCl (150 mL).The aqueous layer was extracted with CH₂Cl₂ (2×25 mL), and the combinedorganic layer was concentrated under reduced pressure to give a reddishyellow residue, which was dried on the vacuum line for 1 hour at roomtemperature and the resulting reddish yellow crude solid product wasused directly in the following reaction without further purification.

Synthesis of WBI-PC-63

To the aldehyde intermediate B was added glacial acetic acid (150 mL)followed by cyanoacetic acid (11.0 g, 0.129 mol) and ammonium acetate(12.3 g, 0.160 mol), and the reaction was refluxed for 5 hours. Thereaction was then cooled to room temperature, and was then slowly addedto ice-cold DI water (1.5 L), and stirred at room temperature for 1hour. The precipitate was filtered and washed with DI water and hexanes,and dried overnight in a vacuum oven at 60° C. to afford WBI-PC-63 as adark red solid. (31.5 g; 95% overall yield). LCMS (M+1): 615.3; 1H NMR(400 MHz, d6-DMSO): 8.52 (s, 1H), 7.85 (s, 1H), 7.46-6.86 (m, 15H), 3.94(s, 3H), 3.83 (s, 3H), 1.26 (s, 18H).

Example 2 Synthesis of(Z)-2-cyano-3-[4-[(E)-2-[4-(N-phenylanilino)phenyl]vinyl]phenyl]prop-2-enoicAcid (WBI-PC-64)

Synthetic Scheme:

Synthesis of Olefin Intermediate A

The starting aldehyde (4.5 g, 0.0165 mol) was placed in a pear shapedflask with 25 mL of dry THF and the yellow solution was degassed for 20min with N₂.KOtBu (2.5 g, 1.25 equiv.) and methyltriphenylphosphoniumiodide (8.33 g, 1.25 equiv.) were combined in a separate 250 mL Schlenckflask equipped with a stirbar and placed under N₂. The THF solution of Awas then canula transferred under N₂ into the Schlenck flask. Thesolution was stirred at room temperature under N₂ for 5 hr. The reactionmixture was partitioned between 125 mL of CH₂Cl₂ and 100 mL of DI water.The mixture was acidified using concentrated HCl (pH˜4). The separatedorganic layer was then washed with DI water (2×100 mL) and thensaturated brine solution (100 mL). The combined organic layer was thendried over anhydrous Na₂SO₄ and concentrated under reduced pressure. 1HNMR of the crude product confirmed the formation of the desired Wittigproduct. The crude material was then purified on silica gel usingn-hexanes as the eluent to afford 3.10 g of olefin product A as a whitesolid (78% yield).

Synthesis of Aldehyde Intermediate B

A Schlenck flask was charged sequentially with A (1.00 g, 3.69 mmol),4-bromobenzaldehyde (310 mg, 1.68 mmol), Pd₂(dba)₃ (15 mg), sodiumcarbonate (444 mg, 1.13 equiv.), and 2,6-di-t-butylcresol (732 mg, 0.33mmol). The reaction mixture was then treated with dry dimethylacetamide(DMAC, 10 mL) and the flask flushed with N₂ for 20 min at roomtemperature. The reaction was then placed in an oil bath at 120° C.under N₂ for 24 hours. The color of the solution changed from lightyellow to dark yellow. The reaction was stopped and CH₂Cl₂ (100 mL) wasadded, and washed with of DI water (2×100 mL). The organic layer waswashed with saturated brine solution (100 mL), dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The crude product wasthen purified on silica gel using hexanes/CH₂Cl₂ (85:15) as the eluentto give the desired aldehyde product B as a yellow solid (600 mg, 45%yield).

Synthesis of WBI-PC-64

Combined B (404 mg, 1.076 mmol) was treated with cyanoacetic acid (92mg, 1 equiv.) and piperidine (0.22 mL, 2 equiv.) in 30 mL of dry MeCNand flushed with N₂ at room temperature for 15 min. The reaction flaskwas then placed into an oil bath (82° C.) and refluxed under N₂ for 18hours. The reaction turned from yellow to orange red and becamehomogeneous. The reaction was stopped, allowed to cool to roomtemperature and the solvent removed under reduced pressure. The residuewas placed in a separatory funnel with 100 mL of CH₂Cl₂. The organiclayer was washed with 0.1 N HCl solution (100 mL) and DI water (100 mL).The organic layer was then dried over anhydrous Na₂SO₄ and dried underreduced pressure to yield WBI-PC-64 (350 mg, 79% yield) as dark redcrude product. LCMS (M+1): 443.1; 1H NMR (400 MHz, d6-DMSO): 8.29 (s,1H), 8.10 (s, 2H), 7.75 (s, 2H), 7.32-6.92 (m, 16H).

Example 3 Synthesis of(E)-2-cyano-3-[4-[(E)-2-[4-(3,6-ditert-butylcarbazol-9-yl)phenyl]vinyl]-2,5-dimethoxy-phenyl]prop-2-enoicAcid (WBI-PC-66)

Synthetic Scheme:

Synthesis of Olefin Intermediate A

Bis(3,6-t-butyl)carbazole (0.0053 mol) and 4-bromostyrene (˜0.7 mL,10.0053 mol, equiv.) were combined in an oven dried 100 mL Schlenckflask with Pd₂(dba)₃ (48 mg, 0.0533 mmol), phosphine (36 mg, 1.06 mmol)and NaOtBu (0.56 g, 0.0059 mol). The flask was flushed with N₂ for 10min, then dry, degassed 1,4-dioxane (10 mL) was added and the reactionwas heated at 80° C. for 1.5 hours under N₂. The reaction was monitoredby TLC to confirm consumption of starting materials and then cooled toroom temperature. The organic layer was washed with DI water (2×25 mL),then saturated brine solution (25 mL). The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingcrude olefin intermediate A was used in the following step withoutfurther purification.

Synthesis of Aldehyde Intermediate B

The olefin intermediate A (5.0 mmol) was mixed with 4-bromo benzaldehyde(1.39 g, 5.0 mmol, 1.5 equiv.) in a 100 mL Schlenck vessel with drytoluene (30 mL) and flushed with N₂ for 20 min. To this solution wereadded Pd(dba)3 (92 mg, 2 mol %), tricyclohexylphosphine (57 mg, 4 mol %)and NaOtBu (724 mg, 1.5 equiv.) under N₂. The reaction mixture was thenrefluxed for 18 hours under N₂. The reaction was stopped and allowed tocool to room temperature. The mixture was treated with DI water (25 mL),the organic layer was then washed sequentially with 1N HCl (25 mL) andsaturated brine (25 mL) solution. The organic layer was concentratedunder reduced pressure and purified on silica gel column usingHexanes:DCM to give the aldehyde product B as a yellow solid (2.54 g,78% yield).

Synthesis of WBI-PC-66

The aldehyde intermediate B (0.82 g, 2.70 mmol, oily solid) was placedin a RB flask with cyanoacetic acid (505 mg, 2.2 equiv.). Piperidine(1.23 mL, 4.6 equiv.) was added with 15 mL of dry MeCN. The mixture wasplaced under N₂ and stirred for 15 min. The mixture was then refluxedfor 12 hours under N₂. The reaction was stopped and the MeCN wasconcentrated under reduced pressure to yield a residue. The residue wasdissolved in 100 mL of EtOAC and washed with 50 mL of DI water. Theorganic layer was then washed with 0.1N HCl (75 mL). The organic layerwas then analyzed by TLC and DART/MS (negative ion mode) and productformation was confirmed. The organic layer was concentrated underreduced pressure and the crude product was purified on silica gel usingDCM:MeOH (100:0 to 90:10) to afford WBI-PC-66 as a yellowish red solid.1H NMR (400 MHz, d6-DMSO) δ 8.54 (s, 1H), 8.29 (d, 2H), 7.89- (m, 10H),5.75 (s, 2H), 3.98, 3.88 (2s, 3H), 1.41 (s, 18H).

Example 4 Synthesis of(Z)-2-cyano-3-[5-[4-(N-phenylanilino)phenyl]-2-furyl]prop-2-enoic Acid(WBI-PC-81)

Synthetic Scheme:

Synthesis of Aldehyde Intermediate A

A mixture of 4-bromo-N,N-diphenyl-aniline (1.0 g, 3.08 mmol),PdCl₂(dppf) (250 mg, 10 mol %), K2CO3 (2.12 g, 5 equiv.) were combinedwith 15 mL of dry toluene in a Schlenck tube and stirred under N₂ for 15min at room temperature. The mixture was treated with(5-formyl-2-furyl)boronic acid (964 mg, 2 equiv.) in dry MeOH (5 mL),and the reaction was refluxed for 18 hours under N₂. The mixture wasthen cooled to room temperature and the solvents were removed underreduced pressure. The resulting residue was treated with DI water (20mL) and extracted with DCM (50 mL). The organic layer was sequentiallywashed with DI water (20 mL), 1N HCl (25 mL) and saturated brinesolution (25 mL). The organic layer was concentrated under reducedpressure and purified on silica gel using Hexanes: EtOAc as eluent toafford 5-[4-(N-phenylanilino)phenyl]furan-2-carbaldehyde (A) as a yellowred solid (900 mg, 82% yield).

Synthesis of WBI-PC-81

5-[4-(N-phenylanilino)phenyl]furan-2-carbaldehyde A (640 mg, 1.80 mmol)was combined with cyanoacetic acid (382 mg, 2.5 eq) and piperidine(0.931 mL, 2.1 eq with respect to cyanoacetic acid) in 10 mL of dryMeCN. The reaction was refluxed for 4 hours whereby the TLC indicatedconsumption of all starting material. The reaction was cooled down toroom temperature and the MeCN was removed under reduced pressure. To theresidue was added EtOAc (50 mL), washed with DI water (50 mL) followedby 0.1 N HCl (50 mL). The organic layer was separated, concentrated andthen the crude mixture was then purified using a silica gel column usingDCM: MEOH as eluent to afford WBI-PC-81 as a dark red solid (600 mg, 79%yield). LCMS (M+1): 407.1; 1HNMR (400 MHz, d6-DMSO) 7.99 (s, 1H), 7.77(s, 2H), 7.60 (s, 1H), 7.40 (m, 4H), 7.22-7.08 (m, 7H), 6.94 (s, 2H).

Example 5 Synthesis of7-[(E)-2-[4-(4-tert-butyl-N-(4-tert-butylphenyl)anilino)phenyl]vinyl]-2-oxo-1H-quinoline-3-carbonitrile(WBI-PC-174)

Synthetic Scheme:

Synthesis of Olefin Intermediate A

To a mixture of Bis((4-t-butyl)phenyl)amine (15.0 g, 0.053 mol) and4-bromostyrene (˜7 mL, 1 equiv.) in an oven dried 500 mL Schlenck flaskwas added Pd₂(dba)₃ (488 mg, 0.533 mmol), phosphine (360 mg, 1.06 mmol)and NaOtBu (5.63 g, 0.059 mol). The flask was flushed with N₂ for 10 minand treated with degassed 1,4-dioxane (50 mL) was added, and the mixturewas heated at 80° C. for 1.5 hours under N₂. The reaction was monitoredby TLC for completion before cooling to room temperature. The organiclayer was washed with DI water (2×100 mL) and then saturated brinesolution (100 mL). The organic layer was then dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The resulting crudeolefin product was used in the following step without furtherpurification.

Synthesis of WBI-PC-174

1.0 equiv. of 7-bromo-2-oxo-1H-quinoline-3-carbonitrile, 0.025 equiv.Pd₂(dba)₃ and 0.05 equiv. tBu3PHBF4 were added to 1.0 equiv. ofN,N-bis(4-tert-butylphenyl)-4-vinyl-aniline in a round bottom flask. Theflask was purged with N₂ for 20 min. Dry dioxane was degassed bybubbling with N₂ for 20 minutes. Dioxane was added to the reaction (0.2M) followed by 1.5 equiv. N-methyl-di-cyclohexyamine. The solution washeated to 65° C. and monitored by LCMS, TLC 30% ethyl acetate/hexane.After 1.5 hours the reaction had solidified. 4.0 mL of N₂ degassed drydioxane were added to redissolve the material and the styrene wasconsumed within 2.5 hours as indicated by TLC. The reaction mixture, asolid mass, was cooled to room temperature, residual solvent was removedunder reduced pressure. The crude reaction product was partitionedbetween 50 mL of CH₂Cl₂ and 20 mL of 1M HCl and the insoluble materialwas filtered off. The layers were separated, and the aqueous layer wasback extracted 2×25 mL of CH₂Cl₂. The combined organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure to affordWBI-PC-174. 1HNMR (400 MHz, d6-DMSO) 8.10 (s, 1H), 7.60-6.91 (m, 17H),1.26 (s, 18H).

General Synthetic Scheme for Making Compounds with Acid Linkers

Example 6 Synthesis of(Z)-3-[2-(carboxymethoxy)-4-[(E)-2-[4-(N-phenylanilino)phenyl]vinyl]phenyl]-2-cyano-prop-2-enoicAcid (WBI-PC-78)

Synthetic Scheme:

Synthesis of the Bromoaldehyde Intermediate with Acid Linker (A)

A mixture of 4-bromo-2-hydroxybenzaldehyde (1.5 g, 7.4 mmol), tert-butyl6-bromohexanoate (9.0 mmol) and potassium carbonate (3.2 g, 22.5 mmol)were taken in acetone (10 mL). The reaction mixture was refluxed for 4h. The reaction mixture was extracted with ethyl acetate (2×25 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure.Purification on silica gel afforded 1.1 g of the desired compound A as awhite solid.

Synthesis of the Aldehyde Intermediate with Acid Linker (B)

To the N,N-diphenyl-4-vinyl-aniline (0.003 mol) in a two necked flaskunder N₂ was added the bromo-aldehyde intermediate A (0.004 mol) andN-methyl-dicylohexyl amine (0.008 mol). Pd₂(dba)₃ (0.04 g, 0.044 mmol)and phosphine salt (0.022 g, 0.007 mmol) were then added to the flaskunder N₂. Dry and degassed 1,4-dioxane (10 mL) was added to the flask.The mixture was stirred at 70° C. under N₂ for 2.5 hours. The reactionmixture was extracted with ethyl acetate, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. Purification on silica gelafforded 1.4 g of the desired compound B.

Synthesis of WBI-PC-78

In a 20 mL microwave tube, the intermediate B (3 mmol), 2-cyanoaceticacid (5.1 mmol) and ammonium acetate (8 mmol) were mixed in acetic acid(15 mL). The reaction mixture was heated at 130° C. for 90 min. Water(10 mL) was added, and the solid was filtered, and dried under reducedpressure to give the product WBI-PC-78. LCMS (M+1): 559.7; 1H NMR (400MHz, d6-DMSO) 8.54 (s, 1H), 8.17 (s, 1H), 7.32-7.30 (m, 9H), 7.06-7.03(m, 9H), 4.19 (t, 2H), 2.47 (t, 2H), 1.88-1.66 (m, 4H).

Example 7 Synthesis of(Z)-3-[2-(carboxymethoxy)-4-[(E)-2-[4-(N-phenylanilino)phenyl]vinyl]phenyl]-2-cyano-prop-2-enoicAcid WBI-PC-190

Synthetic Scheme:

Synthesis of the Bromoaldehyde Intermediate with Acid Linker

In a 250 mL round bottom flask, 4-bromo-2-hydroxybenzaldehyde (3 g, 14.9mmol), tert-Butyl bromoacetate (3.49 g, 17.9 mmol) and potassiumcarbonate (6.19 g, 44.8 mmol) were dissolved in acetone (30 mL). Thereaction mixture was refluxed for 4 hours. The reaction mixture was thenextracted with ethyl acetate (2×25 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. Purification on silica gel afforded2.8 g (59% yield) of the desired compound A as white solid. 1H NMR (400MHz, CDC 3): 10.46 (s, 1H), 7.71 (d, 1H), 7.24 (s, 1H), 6.99 (s, 1H),4.61 (s, 2H), 1.47 (s, 9H).

Synthesis of the Aldehyde Intermediate with Acid Linker

To the N,N-diphenyl-4-vinyl-aniline (2 g, 0.007 mol) in a two neckedflask under N₂ was added 4-bromo-2,5-dimethoxy benzaldehyde (2.44 g,0.008 mol) and N-methyl-di-cyclohexyl amine (3.3 mL, 0.016 mol).Pd₂(dba)₃ (0.081 g, 0.088 mmol) and phosphine salt (0.043 g, 0.0014mmol) were then added to the flask under N₂. Dry and degassed1,4-dioxane (10 mL) was added to the flask. The mixture was stirred at70° C. under N₂ for 2.5 hours. The mixture turned from purple to yellowgreen upon stirring. TLC analysis (Hex:Ethyl acetate 10:1) after 2.5hours showed complete consumption of 4-bromo-2,5-dimethoxy benzaldehydeand the formation of the desired product (confirmed by LCMS). Thereaction mixture was extracted with ethyl acetate, dried over anhydrousNa₂SO₄ and evaporated. Purification by combiflash afforded 2.2 g ofdesired compound B. LCMS (M+1): 505.9; 1H NMR (400 MHz, CDCl₃): 10.48(s, 1H), 7.80 (d, 1H), 7.40-7.04 (m, 19H), 6.99 (s, 1H), 4.67 (s, 2H),1.47 (s, 9H).

Synthesis of WBI-PC-190

In a 20 mL microwave tube, tert-butyl 2-[2-formyl-5-[(E)-2-[4-(Nphenylanilino)phenyl]vinyl]-phenoxy]-acetate (1.3 g, 3 mmol),2-cyanoacetic acid (0.46 g, 5.1 mmol) and ammonium acetate (0.595 g, 8mmol) were mixed in 15 mL of acetic acid. The reaction mixture washeated at 130° C. for 20 min. LCMS showed desired mass peak along withtertiary group deprotected product. Water (10 mL) was added, and thesolid was filtered, and dried under reduced pressure to give the productWBI-PC-190 (0.6 g, 83% yield) red solid. LCMS (M+1): 516.6; 1H NMR (400MHz, d6-DMSO): 8.60 (s, 1H), 8.18 (s, 1H), 7.34-6.98 (m, 20H), 4.92 (s,2H).

Example 8 Synthesis of WBI-PC-191 Synthesis oftert-Butyl-8-bromooctanoic Acid Intermediate

To a solution of 8-bromooctanoic acid (5 g, 22 mmol) in DCM (20 mL) wasadded TFAA (10.36 g, 49 mmol) dropwise at 0° C. After 2.5 hours, t-BuOH(5.81 g, 70 mmol) was slowly added. After 1 hour, the reaction hadwarmed to rt. After 2.5 hours, the reaction was quenched with H2O (10mL) and extracted with ethyl acetate (2×20 mL). The combined organiclayer was washed with brine and dried over MgSO₄, filtered, andconcentrated under reduced pressure. The crude (6.89 g) was used in thenext step without further purification.

Synthesis of the Aldehyde Intermediate by O-alkylation of4-bromo-2-hydroxy-benzaldehyde with Tert-Butyl Ester Linker

In a single necked round bottom flask, 4-bromo-2-hydroxy-benzaldehyde (3g, 0.015 mol), tert-butyl 8-bromooctanoate (4.16 g, 0.015 mol) and K2CO3(4.12 g, 0.03 mol) were dissolved in dry DMF (30 mL). The reactionmixture was heated at 70° C. for 16 hours. LCMS showed the desired masspeak. The crude reaction mixture was extracted with ethyl acetate,washed with water, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. Purification on silica gel using Hexane/Ethyl acetate(97:3) afforded 2.4 g (40% yield) of desired product. 1H NMR (400 MHz,CDCl3): 10.39 (s, 1H), 7.67 (d, 1H), 7.11 (d, 2H), 4.03 (t, 2H), 2.21(t, 2H), 1.80-1.23 (m, 10H), 1.41 (s, 9H).

Synthesis of the Triphenylamine Styryl Aldehyde Intermediate Tert-ButylEster Linker Product

To the N,N-diphenyl-4-vinyl-aniline (2 g, 0.007 mol) in a two neckedflask under N₂ was added tert-butyl8-(5-bromo-2-formyl-phenoxy)octanoate (3.09 g, 0.008 mol) andN-methyl-dicylohexyl amine (3.05 g, 0.0.016 mol). Pd₂(dba)₃ (0.081 g,0.088 mmol) and phosphine salt (0.043 g, 0.0014 mmol) were then added tothe flask under N₂. Dry and degassed 1,4-dioxane (10 mL) was added tothe flask. The mixture was stirred at 70° C. under N₂ for 2.5 hours. Themixture turned from purple to yellow green upon stirring. TLC analysis(Hexane:Ethyl acetate 10:1) after 2.5 hours showed complete consumptionof tert-butyl 8-(5-bromo-2-formyl-phenoxy)octanoate and the formation ofthe desired product (confirmed by LCMS). Purification on silica gelafforded 2.3 g (50% yield) of the desired product. 1H NMR (400 MHz,CDCl₃): 10.40 (s, 1H), 7.66 (d, 1H), 7.13 (d, 2H), 4.04 (t, 2H), 2.19(t, 2H), 1.81-1.28 (m, 14H), 1.41 (s, 9H).

Synthesis of the Cyanoacrylic Acid Intermediate by KnoevenaqelCondensation

In a 20 mL microwave tube, tert-butyl8-[2-formyl-5-[(E)-2-[4-(N-phenylanilino)phenyl]vinyl]phenoxy]octanoate(1.5 g, 3 mmol), 2-cyanoacetic acid (0.454 g, 5 mmol) and ammoniumacetate (0.588 g, 8 mmol) were dissolved in 15 mL of acetic acid. Thereaction mixture was heated at 130° C. for 20 min. LCMS showed thedesired mass peak along with tertiary group deprotected product. Water(10 mL) was added and filtered. The collected solid was used in the nextstep without further purification.

Synthesis of WBI-PC-191 by Tert-Butyl Deprotection

In a 20 mL microwave tube,(Z)-3-[2-(8-tert-butoxy-8-oxo-octoxy)-4-[(E)-2-[4-(N-phenylanilino)phenyl]vinyl]phenyl]-2-cyano-prop-2-enoicacid (1 g, 1.52 mmol) was dissolved in 10 mL acetic acid and 1 mL water.The reaction mixture was heated at 130° C. for 20 min. The reaction wasrepeated two times for 20 min each in the microwave. LCMS showed thedesired mass peak. Water (10 mL) was added and filtered. The collectedsolid was dried under reduced pressure to give WBI-PC-191 0.650 g (61%yield) as a red solid. LCMS (M+1): 600.7; 1H NMR (400 MHz, d6-DMSO):8.56 (s, 1H), 8.18 (s, 1H), 7.60-6.91 (m, 20H), 4.16 (br s, 2H), 2.18(br s, 2H), 1.89 (br s, 2H), 1.58-1.20 (m, 8H).

Example 9 Synthesis of WBI-PC-192 Synthesis of thetert-Butyl-10-bromodecanoic Acid Intermediate

To solution of 10-bromdectanoic acid (5 g, 20 mmol) in DCM (20 mL) wasadded TFAA (9.2 g, 44 mmol) dropwise at 0° C. After 2.5 hours, t-BuOH(5.16 g, 70 mmol) was slowly added. After 1 hour the reaction had warmedto RT. After 2.5 hours, the reaction was quenched with H2O (5 mL) andextracted with ethyl acetate (2×20 mL). The combined organic layer waswashed with brine and dried over MgSO₄, filtered, and concentrated underreduced pressure. The crude (6.12 g) was used in the next step withoutfurther purification.

Synthesis of the Aldehyde Intermediate by O-alkylation of4-bromo-2-hydroxy-benzaldehyde with Tert-Butyl Ester Linker

In a single necked round bottom flask, 4-bromo-2-hydroxy-benzaldehyde (3g, 0.015 mol), tert-butyl 10-bromodecanoate (5.04 g, 0.016 mol) andK2CO3 (6.18 g, 0.045 mol) were dissolved in dry DMF (30 mL). Thereaction mixture was heated at 70° C. for 16 hours. LCMS showed thedesired mass peak. The crude reaction mixture was extracted with ethylacetate, washed with water, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. Purification on silica gel afforded 3.2 g (50%yield) of the desired product.

Synthesis of the Triphenylamine Styryl Aldehyde Intermediate Tert-ButylEster Linker

To the N,N-diphenyl-4-vinyl-aniline (2 g, 7.74 mmol) in a two neckedflask under N₂ was added tert-butyl10-(5-bromo-2-formyl-phenoxy)decanoate (3.307 g, 7.75 mmol) andN-methyl-dicylohexyl amine (3.05 g, 15.56 mmol). Pd₂(dba)₃ (0.081 g, 0.8mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.043 g, 1.4mmol) were then added to the flask under N₂. Dry and degassed1,4-dioxane (10 mL) was added to the flask. The mixture was stirred at70° C. under N₂ for 2.5 hours. The mixture turned from purple to yellowgreen upon stirring. TLC analysis (Hexane:Ethyl acetate 10:1) after 2.5hours showed complete consumption of tert-butyl10-(5-bromo-2-formyl-phenoxy)decanoate and the formation of the desiredproduct (confirmed by LCMS). Purification on silica gel afforded 2.3 gof desired product as a yellow liquid. 1H NMR (400 MHz, d6-DMSO): 10.43(s, 1H), 7.82 (s, 1H), 7.41-6.98 (m, 16H), 4.10 (t, 2H), 2.20 (t, 2H),1.90-1.209 (m, 14H), 1.42 (s, 9H).

Synthesis of the Cyanoacrylic Acid Intermediate by KnoevenaqelCondensation

In a 20 mL microwave tube, tert-butyl10-[2-formyl-5-[(E)-2-[4-(N-phenylanilino)phenyl]vinyl]phenoxy]-decanoate(1.5 g, 2.43 mmol), 2-cyanoacetic acid (0.434 g, 5.1 mmol) and ammoniumacetate (0.561 g, 7.23 mmol) were dissolved in 15 mL acetic acid. Thereaction mixture was heated at 130° C. for 20 min. LCMS showed thedesired mass peak along with the tertiary group deprotected product.Water (10 mL) was added and filtered. The collected solid was used inthe next step without further purification.

Synthesis of WBI-PC-192 by Tert-Butyl Deprotection

In a 20 mL microwave tube,(Z)-3-[2-(10-tert-butoxy-10-oxo-decoxy)-4-[(E)-2-[4-(N-phenylanilino)-phenyl]vinyl]phenyl]-2-cyano-prop-2-enoicacid (0.9 g, 1.31 mmol) was dissolved in 20 mL of acetic acid. Thereaction mixture was heated at 130° C. for 20 min. The reaction wasrepeated two times for 20 min each in the microwave. LCMS showed thedesired mass peak. Water (10 mL) was added and filtered. The collectedsolid was dried under reduced pressure to give 0.650 g (61% yield) ofWBI-PC-192 as a red solid. LCMS (M+1): 628.7; 1H NMR (400 MHz, d6-DMSO):8.54 (s, 1H), 8.19 (s, 1H), 7.61-6.90 (m, 20H), 4.18 (br s, 2H), 2.20(br s, 2H), 1.88 (br s, 2H), 1.58-1.20 (m, 12H).

Example 10 Biological Testing

Materials

Human peptides Aβ1-42 and Amylin 8-37 were purchased from China Peptideand stored at −80° C. Zinc sulfate heptahydrate (ZnSO₄.7H2O), BisANS(4,4′-Dianilino-1,1′-binaphthyl-5,5′-disulfonic acid dipotassium salt),Epigallocatechin-3-gallate (EGCG), 9-(Dicyanovinyl)julolidine (DCVJ) andClioquinol (CQ) were purchased from Sigma Aldrich.Ethylenediaminetetraacetic acid (EDTA) was purchased from Alfa Aesar.2-(dimethylamino)methyl-5,7-dichloro-8-hydroxyquinoline (AC-068),structurally similar to PBT-2 was synthesized by Warner BabcockInstitute for Green Chemistry, LLC.

Fluorescence-Based Assays of Aβ Disaggregation

As disaggregation was assessed using a Spectramax M5 multi-modemicroplate reader (Molecular Devices) using untreated black 96-wellplates (Costar #3915). The device was configured to maintain 26° C.,measure an excitation of 390 nm, emission of 490 nm and cutoff 475 nmwith the PMT+set at Medium, 6 flashes/read at 40 second intervals withshaking 5 seconds before the first read and 3 seconds between reads.

Experiments were conducted at 26° C. in a Tris-HCl buffer (50 mM, pH7.4)containing NaCl (150 mM). Aβ1-42 was solubilized in DMSO to aconcentration of 1.5 mM for 5 minutes then briefly centrifuged to removeany aggregates. The soluble Aβ1-42 (15 μM) was immediately mixed±bis-ANS (15 μM) and allowed to equilibrate for 5 minutes. Aβaggregation was induced with the addition of ±Zn (15 μM) in H2O. Thefluorescence response was measured until a plateau was reached atapproximately 45 minutes. Test compounds (0.227-60 μM in DMSO) were thenadded and the dose response was measured over a 20-minute period. EDTA,known to chelate Zn, was used as a positive control. Raw fluorescencewas normalized to background fluorescence without Aβ and expressed as apercentage of that in control samples without Zn. All quantitative datawas expressed as mean±SEM from at least 3 replicates. All statisticalanalysis was conducted with Prism 6 (GraphPad). Nonlinear regression wasused to calculate the concentration at which fluorescence was reduced by50 percent (EC₅₀), as shown in Table 1.

TABLE 1 EC₅₀ values of Aβ1-42:Zn disaggregation by select compoundsCompound EC₅₀ (Avg) StDev PC-063 31.041 16.945 PC-064 0.747 0.090 PC-0781.376 0.110 PC-081 0.338 0.031 PC-174 49.650 238.498 PC-190 0.649 0.072PC-191 1.613 0.281 PC-192 2.848 0.550 CQ 2.693 0.196 DCVJ 0.533 0.188EDTA 46.120 38.551 AC- 2.215 0.271 068(PBT2)Fluorescence-Based Assays of Amylin Disaggregation

Amylin disaggregation was assessed using a Spectramax M5 multi-modemicroplate reader (Molecular Devices) using untreated black with clearbottom 96 well plates (Costar #3631). The device was configured tomaintain 26° C., measure an excitation of 390 nm, emission of 490 nm andcutoff 475 nm with the PMT+set at Medium, 6 flashes/read at 5-minuteintervals with shaking 5 seconds before the first read and 3 secondsbetween reads.

Experiments were conducted at 26° C. in a Tris-HCl buffer (50 mM, pH7.4)containing NaCl (150 mM). Amylin 8-37 peptide was solubilized in DMSO toa concentration of 1.5 mM for 5 minutes then briefly centrifuged toremove any aggregates. The soluble amylin peptide (15 μM) wasimmediately mixed ±bis-ANS (15 μM) and the plate sealed to preventevaporation. Aggregation was measured by an increase in fluorescenceover 24 hours. Test compounds (0.227-60 μM in DMSO) were then added andthe dose response was measured over a 24 hour period. EGCG was used as apositive control. Raw fluorescence was normalized to backgroundfluorescence without Amylin and expressed as a percentage of that incontrol samples. All quantitative data was expressed as mean±SEM from atleast 3 replicates. All statistical analysis was conducted with Prism 6(GraphPad). Nonlinear regression was used to calculate the concentrationat which fluorescence was reduced by 50 percent (EC₅₀), as shown inTable 2.

TABLE 2 EC₅₀ values of Amylin Disaggregation by select compoundsCompound EC₅₀ StdDev PC-063 1.259 0.693 PC-064 0.024 0.043 PC-066 1.1910.309 PC-081 0.207 0.111 PC-174 3.740 6.464 CQ 4.074 3.036 EGCG 0.8570.491

What is claimed is:
 1. A compound of formula I:

wherein R⁶ is —NR³R⁴; R⁵ is —(CR═CR—)_(n)(CR═CR²—)R¹; n is an integerfrom 0 to 10; R¹ and R² are independently selected from the groupconsisting of —H, —CN, —COOR, CONHR, CON(H)OR, —SO₃R, —SO₂R—OSO₃R,—PO₃HR, and —OPO₃HR, further wherein at least one of R¹ and R² is not—H; each R is independently selected from —H and C₁₋₆ linear or branchedalkyl; and R³ and R⁴ are independently selected from the groupconsisting of H, substituted or unsubstituted linear or branched C₁-C₁₀alkyl, substituted or unsubstituted phenyl, substituted or unsubstitutedC₆-C₁₀ aryl, substituted or unsubstituted C₅-C₁₀ heteroaryl, substitutedor unsubstituted C₅-C₁₀ cycloalkyl, and substituted or unsubstitutedC₅-C₁₀ heterocycloalkyl; or R³ and R⁴ attached to their N together forma ring that is substituted or unsubstituted C₅-C₁₀ heterocycloalkyl,provided that if n=0, and R³ and R⁴ are both: (a) H; (b) substituted orunsubstituted linear or branched C₁-C₁₀ alkyl; or (c) substituted orunsubstituted phenyl or C₆-C₁₀ aryl, then R¹ and R² are not bothselected from the group consisting of —H, —CN, —COOR, —PO₃HR, and—CONHR.
 2. The compound of claim 1 having the formula II:


3. The compound of claim 1 having the formula III:


4. The compound of claim 1 having the formula IV:


5. The compound of claim 1 wherein R⁶ is selected from the groupconsisting of diethylamino, diphenylamino, methyl(phenyl)amino,cyclohexyl(methyl)amino, bis(4-methoxyphenyl)amino,bis(4-(tert-butyl)phenyl)amino, di(pyridin-2-yl)amino,di(pyridin-3-yl)amino, di(pyridin-4-yl)amino, piperidin-1-yl,4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl, pyrrolidin-1-yl, andmorpholino.
 6. The compound of claim 1 wherein R³ and R⁴ are substitutedor unsubstituted phenyl.
 7. The compound of claim 4 wherein R¹ and R²together are —CN and —COOH.
 8. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 and apharmaceutically acceptable excipient.